Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic, debilitating clinical syndrome presenting as severe pelvic pain with extreme urinary urgency and frequency in the absence of any known cause. The etiologic mechanisms underlying PBS/IC are unknown, but recurrence risks to siblings of affected individuals, concordance among monozygotic twins, and our own preliminary studies indicate a strong genetic contribution to the cause of PBS/IC. The overall goal of this proposal is to identify the genes containing mutations that result in PBS/IC and determine how the different encoded proteins of these genes interact with one another in a common biological pathway. Ultimately, understanding how mutations in up to five different genes yield the symptoms of PBS/IC should lead to improved diagnosis and possible therapies. We plan to attain our goals via the following specific aims: 1) Accurately characterize PBS/IC patients and their family members and enroll them in our genetic studies. Carefully evaluated cohorts of patients and their families are essential to the discovery of the genetic variation underlying PBS/IC. 2) Map the locations of PBS/IC genes by linkage analysis in families in which PBS/IC is segregating. We have already recruited several families with autosomal dominant inheritance of PBS/IC and identified linkage peaks in the most informative pedigrees. 3) Identify within linked regions of the genome the first genes that control inherited risk of PBS/IC and correlate the types of mutations with clinical symptoms. 4) Determine how proteins encoded by these PBS/IC genes interact with one another. Such knowledge should yield a better understanding of the biochemical or developmental pathways leading to PBS/IC. PUBLIC HEALTH RELEVANCE: Painful bladder syndrome/interstitial cystitis (PBS/IC) is a severe, chronic, debilitative clinical syndrome with pelvic pain, extreme urinary urgency and frequency without a known underlying cause. This proposal should lead to a better understanding of the genetic components of the disorder and the underlying biochemical and developmental pathways leading to PBS/IC. Such knowledge could lead to improved diagnosis and rational design of therapeutic interventions.